The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. A central feature of IBD epidemiology is the 4.3-7.7 fold increased prevalence of disease in Ashkenazi Jewish populations. It is unknown at present what factors account for this higher disease prevalence. This proposal will address this gap through testing two hypotheses. First, we hypothesize that uncommon variation of higher effects not well assayed by present genome-wide association study (GWAS) platforms contributes to IBD in Ashkenazi Jewish populations. An alternative hypothesis is that positive selection in the Ashkenazim, possibly involving a functional network of multiple loci involving common alleles, significantly contributes to the higher disease prevalence. Preliminary data are provided detailing a) the genetic architecture of IBD, with the unique absence of a dominant major histocompatibility complex in Crohn's disease, b) the precise nature of the population substructure between Jewish and non-Jewish European ancestry cohort, c) results of a genome-wide association study in Ashkenazi Jewish Crohn's disease which demonstrate a largely similar genetic architecture for common alleles, d) exome sequencing results in Jewish Crohn's disease cases, demonstrating the presence of uncommon alleles unique to the Ashkenazim, e) the present inadequacy of present reference sequences in critical immunoregulatory regions such as the KIR region on chromosome 19p13, f) enrichment of immune-mediated association signals in Th17-enriched cell subsets, and g) the improved molecular resolution achieved through RNASeq. A complete exploration of the underlying etiology for the markedly increased IBD prevalence in the Ashkenazim will be achieved through the interrogation of uncommon SNPs in the exome and throughout the genome through case control studies (Specific Aim 1). Important in this regard will be the ascertainment of large case-control cohorts, for which additional recruitment is proposed. The presence of uncommon risk alleles in the Ashkenazim might result from genetic drift, given their unique population history. An alternate possibility is that positive selection wthin the Ashkenazim at multiple loci, acting as a functional module, increases risk for IBD, and contributes to the higher disease prevalence compared to non-Jewish European ancestry cohorts. Refined definitions of associated alleles through regression analysis and functional annotation, together with interrogation of weaker effect alleles, will result in an aggregate estimate of the extent to which identified susceptibility alleles account for the higher disease prevalence in the Ashkenazim (Specific Aim 2). As with heritability, these estimates will provide a key measure of assessing the completeness of identified genetic factors in defining disease pathophysiology.